The broad goal of the proposed research is to investigate the pathophysiology of bone loss induced by ionizing radiation. Bones exposed to therapeutic doses of ionizing radiation display reduced mineral density, inferior mechanical strength, premature fatty replacement of red marrow, and are predisposed to insufficiency fractures. The effects of ionizing radiation on the lineage commitment of skeletal stem cells (a subset of marrow stromal cells (BMSCs) also known as bone marrow derived mesenchymal stem cells) is poorly defined, and warrants further study. The experiments that are described in the proposal will determine how radiation impacts the development and cumulative bone forming activity of the osteoblast and its precursor cells. The proposed experiments are designed to test the hypothesis that radiation depletes the osteogenic potential of mesenchymal progenitor cells and promotes adipogenic differentiation as an alternate fate, and that reconstitution of BMSCs will mitigate the structural and metabolic deficits characteristic of irradiated bone. This hypothesis will be tested in three specific aims: (1) Examine depletion of BMSC-derived osteoprogenitors as a factor driving radiation-induced bone loss; (2) Assess P-PAR? as a therapeutic target in radiation-induced bone loss; and (3) Evaluate efficacy of BMSC as a mitigant of radiation-induced bone loss. These aims will be accomplished through the use of mouse models and cell culture experiments in combination with genetic, pharmacologic and cell-based therapeutic strategies. Greater understanding of the adverse effects of ionizing radiation on the multi-lineage differentiation capacity of BMSC may yield new therapeutic targets for the prevention and/or correction of bone loss that may be experienced following radiotherapy.